Overview. The current study proposes to examine gaps in the HIV prevention and treatment cascade among transgender women (TGW) at risk for or living with HIV. Specifically, we will examine a new framework, the SAVAGE syndemic (Substance Abuse, Violence, AIDS/HIV, Gender minority stress, & Economic marginalization), which integrates the effects of syndemic conditions that cut across risk populations with unique factors for TGW to help explain the distinctive HIV epidemic in this population. Significance. TGW are disproportionately burdened by HIV and represent a population in great need of intervention with respect to the HIV prevention and care cascade. Miami, FL (the proposed study site) is a domestic epicenter of the HIV epidemic, is recognized as the city with the highest HIV burden in the U.S., and where TGW are particularly affected. This study is based in Syndemic theory and the Minority Stress Model, positing that interrelated psychosocial and structural problems interact with unique stressors due to one?s gender minority status leading to psychological adversity and, in turn, HIV risk. Additionally, experiencing multiple syndemic conditions in the context of minority stress can take a long-range toll on physical health via sustained pathogenic activation of the physiological stress response. For those uninfected with HIV, such chronic activation amplifies biological vulnerability to HIV infection. There has been a call for multi-faceted interventions to address the complex HIV epidemic among TGW, but biobehavioral frameworks unique to TGW that will inform such interventions are understudied. Further, given the high prevalence and incidence of HIV among TGW, development of frameworks to simultaneously address both primary and secondary prevention is urgently needed, but currently lacking. Objectives & methods. This dissertation study aims to empirically characterize the SAVAGE syndemic driving HIV acquisition and transmission risk among TGW, and to examine the potential biological consequences of experiencing the syndemic. Aim 1 (behavioral) will examine the SAVAGE syndemic and test its association with primary and secondary biobehavioral HIV risk outcomes (condomless sex, needle sharing, sex work) via a cross-sectional psychosocial quantitative assessment collected from a sample of mixed serostatus TGW (N=100). Aim 2 (biological) will investigate the association between the SAVAGE syndemic and rectal inflammation in the context of primary prevention. Accordingly, for the HIV-uninfected TGW (n=50), biomarkers of inflammation will be collected via rectal swabs, which is most biologically relevant to amplified risk of HIV seroconversion. Innovation. This dissertation study proposes a new, holistic framework to contextualize the complex HIV epidemic among TGW. It will also be among the first to integrate a primary prevention biological risk model within a syndemics framework and do so using innovative methods for examining rectal inflammation. Findings from this study will lay foundation for future development of interventions to mitigate HIV risk among TGW. Proposal relevant to NOT-MD-19-001.